Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-10-17
2002-06-11
Seaman, D. Margaret (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C514S307000
Reexamination Certificate
active
06403799
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to chemical methods of preparing intermediates in the synthesis of the protease inhibitor nelfinavir mesylate and its free base, which is useful for treatment of HIV infected individuals.
2. Related Background Art
Treatment of HIV-infected individuals with HIV-protease inhibitors has emerged as an important method for preventing or inhibiting the rapid proliferation of the virus in human tissue. HIV-protease inhibitors block a key enzymatic pathway in the virus resulting in substantially decreased viral loads, which slows the steady decay of the immune system and its resulting deleterious effects on human health. The HIV-protease inhibitor nelfinavir mesylate has shown to be an effective treatment for HIV-infected individuals. Nelfinavir mesylate, and a method for its preparation are disclosed in U.S. Pat. No. 5,484,926, which is incorporated herein by reference.
Other procedures for the preparation of nelfinavir mesylate and its free base have been reported. For example, PCT/JP96/02756 (WO97/11937) discloses the preparation of nelfinavir mesylate and its free base using oxazoline intermediates, which may be obtained from a 1,3-dioxepan-5-ol, or a derivative thereof. PCT/JP96/02757 (WO97/11938) discloses a related method, wherein the 1,3-dioxepan-5-ol is converted to nelfmavir mesylate and its free base via N-benzyloxycarbonyl-amino-butane diol intermediates. Each of these methods reportedly provide some improvement in the efficiency of the preparation of nelfinavir. However, further improvement would be desirable.
SUMMARY OF THE INVENTION
This invention relates to efficient and cost-effective methods for the preparation of nelfinavir mesylate and its free base. Specifically, the methods of this invention comprise the preparation of an oxazoline,
from a tetrahydrofliran
comprising treating the tetrahydrofuran, wherein R
a
is —COR(1) and R
b
is hydrogen, —COR(3), —SO
2
R(2) or a suitable hydroxyl protecting group, with an oxophilic electrophilic reagent in a manner that is effective to provide the oxazoline, wherein R
b
is hydrogen, —COR(3), —SO
2
R(2) or a suitable hydroxyl protecting group and R
c
is H, —COR(3) or —SO
2
R(2); wherein R(1), R(2) and R(3) independently represent a substituted or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl group. Advantageously, the methods of this invention provide nelfinavir mesylate and its free base in relatively high yield and employ fewer synthetic steps than the prior art methods.
This invention also relates to methods for making intermediate compounds that are useful in the method of preparation of nelfinavir mesylate and its free base. In addition, this invention relates to methods for the preparation of chiral starting materials that are useful in the methods for the preparation of nelfinavir mesylate and its free base according to this invention.
DETAILED DESCRIPTION OF THE INVENTION
This invention provides novel and useful methods for the conversion of amino-tetrahydrofuran derivatives to oxazoline intermediates that are useful in the preparation of nelfinavir mesylate and nelfinavir free base. All compounds of the inventive methods of this invention that contain at least one chiral center may exist as single stereoisomers, racemates and/or mixtures of enantiomers and/or diastereomers unless otherwise indicated. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of this invention. Moreover, the scope of this invention is not intended to be limited to reactions of selected isomers. Although the reaction schemes described herein may be illustrated using compounds depicted as a single enantiomer or diastereomer, the methods of this invention are intended to encompass reactions of any isomer or racemic mixture of these compounds.
When used to describe a particular compound, the term “chiral” is used herein to indicate that the compound is substantially enantiomerically and/or diastereomerically pure, for example, as in the term “chiral amino-tetrahydrofuran.” Compounds that are substantially enatiomerically pure contain at least 90% of a single isomer and preferably contain at least 95% of a single isomer. More preferably, the chiral compounds in this invention contain at least 97.5% of a single isomer and most preferably contain at least 99% of a single isomer. Compounds identified herein as single stereoisomers are meant to describe compounds that are present in a form that contains at least 90% of a single isomer. The term “racemic” or “racemic mixture” refers to a mixture of equal amounts of enantiomeric compounds, which encompasses mixtures of enantiomers and/or mixtures of enantiomeric diastereomers.
The method of this invention provides for the conversion of an amino-tetrahydrofuran, I, to an oxazoline, II, as illustrated below:
wherein R
a
is hydrogen or —COR(1)
R
b
is hydrogen, —COR(3), —SO
2
R(2) or a suitable hydroxyl protecting group;
R
c
is hydrogen, —COR(3) or —SO
2
R(2);
wherein R(1), R(2) and R(3) independently represent a substituted or unsubstituted alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl group.
As used herein, the term “alkyl” represents a straight or branched chain alkyl group, preferably having one to eight, more preferably having one to six, and most preferably having from one to four carbon atoms. The term “C
1
-C
6
alkyl” represents a straight or branched alkyl chain having from one to six carbon atoms. Exemplary C
1
-C
6
alkyl groups include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, neo-pentyl, hexyl, isohexyl, and the like. The term “C
1
-C
6
alkyl” includes within its definition the term “C
1
-C
4
alkyl.”
The term “cycloalkyl” represents a group comprising a saturated or partially unsaturated, mono- or poly-carbocyclic ring, preferably having 5-14 ring carbon atoms. Exemplary cycloalkyls include monocyclic rings having from 3-7, preferably 3-6, carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl and the like. An exemplary cycloalkyl is a C
5
-C
7
cycloalkyl, which is a hydrocarbon ring structure containing from five to seven carbon atoms.
The term “aryl” represents a group comprising an aromatic, monovalent monocyclic, bicyclic, or tricyclic radical containing 6, 10, 14, or 18 carbon ring atoms, to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or heteroaryl groups which may be unsubstituted or substituted by one or more of the substituents described below Illustrative examples of aryl groups include, but are not limited to, phenyl, napthyl, anthryl, phenanthryl, fluoren-2-yl, indan-5-yl, and the like.
The term “heterocycloalkyl” represents a group comprising a non-aromatic, monovalent monocyclic, bicyclic, or tricyclic radical, which is saturated or unsaturated, containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ring atoms and which includes 1, 2, 3, 4, or 5 heteroatoms selected from nitrogen, oxygen and sulfur, and to which may be fused one or more cycloalkyl groups, aryl groups, or heteroaryl groups which may be unsubstituted or substituted by one ore more of the substituents described below. Illustrative examples of heterocycloalkyl groups include, but are not limited to azetidinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, tetrahydro-2H-1,4-thiazinyl, tetrahydrofuryl, dihydrofuryl, tetrahydropyranyl, dihydropyranyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl, azabicylo[3.2.1]octyl, azabicylo[3.3.1]nonyl, azabicylo[4.3.0]nonyl, oxabicylo[2.2.1]heptyl, 1,5,9-triazacyclododecyl, and the like.
The term “heteroaryl” represents a group comprising an aromatic monovalent monocyclic, bicyclic, or tricyclic radical, containing 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ring atoms, including 1, 2, 3, 4, or 5 heteroatoms selected from nitrogen, oxygen and sulfur, to which may be fused one o
Borer Bennett C.
Busse Juliette K.
Zook Scott E.
Agouron Pharmaceuticals , Inc.
Seaman D. Margaret
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